(256g) Physical Aging of Hydroxypropyl Methylcellulose Acetate Succinate Spray-Dried Dispersions Using Fast Scanning Calorimetry

Amorphous solid dispersions (ASDs) utilize the glassy state to kinetically stabilize small molecule active pharmaceutical ingredients (APIs) within a polymer matrix, thus enhancing their bioavailability for oral drug delivery. However, the amorphous polymer matrix is subject to physical aging, i.e., a structural relaxation of the system driven by thermodynamic instability. How this process directly impacts API stability in ASDs remains understudied. To address this knowledge gap, we employed fast scanning calorimetry (FSC) to probe the physical aging behavior of spray-dried ASDs. Ritonavir and Carbamazepine were used as the model drugs, and each were spray dried with hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF) at 1, 5, and 10 drug weight percent by mass. The high scanning rates of FSC inhibited mixing effects at high temperatures, allowing for accurate glass transition measurements throughout the experimental protocol. Aging rate calculations showed that despite their expected kinetic stability, ASDs exhibited significant thermodynamic evolution deep in the glassy state (100°C below the glass transition) independent of drug content. Furthermore, the physical aging rate reached a maximum at ~40°C below T_g before decreasing to near-T_g rates. These observations indicate that drug presence has an overall minor influence on HPMCAS physical aging behavior. In particular, the unique devitrification mechanism of HPMCAS through which aging effects were recovered before the glass transition persisted regardless of drug presence. These findings suggest a relaxation mechanism that may promote further aging of the HPMCAS structure in the glassy state, with implications on ASD design, processing, and storage.